The goal of this project is to study the mechanism of chemically induced murine hepatomas and to identify and characterize endogenous and exogenous factors that may control initiation, promotion and progression of these tumors. Topics of present interest are (l) the time course of chemically induced hepatoma formation, and the genetic control of the changing enzyme patterns during this process; (2) isolation and characterization of preneoplastic cell populations; (3) modulating effects of blood flow and oxygen tension on hepatoma formation and development; and (4) the role of genetic predispostion in hepatoma development. Results obtained so far include: (l) diverting the blood from the splanchnic area directly into inferior vena cava, by performing porta-caval shunt operations, resulted in changes in the liver, such as expression of gamma-glutamyltranspeptidase activity and lack of glucose-6-phosphatase activity, similar to those produced by hepatocarcinogens; and (2) transplantation of normal rat hepatocytes into the spleen of isogenic animals resulted in growth of the cells. Similar experiments using preneoplastic hepatocytes obtained by treating newborn rats with a single dose of diethylnitrosamine followed by administration of phenobarbital, are in progress.